Nanoelectromechanical system (NEMS) resonators enable mass detection with exceptional sensitivity. This has recently culminated in mass resolution at the single-molecule level, where simple spectra have been assembled by statistical analysis from only a few hundred molecular adsorption events.
Mass spectrometry (MS)—the identification of species through molecular mass measurements—is an important analytical tool in chemical and biological research. Since its first applications to organic compounds more than a half century ago, it has assumed an increasingly dominant role in the life sciences and medicine and is now arguably a mainstay of proteomics. Critical to such measurements are spectrometers that are capable of high resolution in the very large mass range, such as above several hundred kDa, which is at or beyond the limit of many conventional MS techniques. NEMS-MS has been described previously for example in U.S. Application Publication No. 2012/0272742 and U.S. Pat. Nos. 7,302,856; 8,227,747; 7,989,198; 7,617,736; 7,552,645; 8,044,556; 8,350,578; 7,724,103; 7,555,938; 7,330,795; 6,722,200 and 8,329,452.
NEMS resonators can be used for mass detection of an analyte. Upon adsorption onto a NEMS resonator, analytes can precipitously downshift a resonant frequency of the resonator. Despite the impressive recent improvements in mass resolution and the detection of discrete adsorption events, all measurements to date neither measure the mass of individual analytes, nor can do so in real-time. The reason for this is that the resonant frequency shift induced by analyte adsorption depends upon both the mass of the analyte and its precise location of adsorption upon the NEMS resonator. Until now, it was not possible to measure both mass and position of an adsorbed analyte to a NEMS resonator.
NEMS-MS spectra, albeit not in real time, have previously been achieved by employing the known position-dependent mass responsivity for a doubly-clamped NEMS resonator. See U.S. Pat. No. 8,227,747. In this previous work analytes were delivered such that they accreted uniformly across the device; this foreknowledge allowed the deduction of the constituents of simple mixtures after collection of only several hundred single-molecule adsorption events. (For comparison, conventional mass spectrometry measurements typically involve measurement of ˜108 molecules.) The analysis involved fitting to the statistical ensemble of measured frequency shifts by a rather complex multidimensional minimization procedure to extract the weights of each constituent, that is, to deduce the mass spectrum. These first results provided a conceptual demonstration of the potential of NEMS-MS, but the complexity of this process precluded its application to arbitrarily complex mixtures.